Single prolonged stress enhances hippocampal glucocorticoid receptor and phosphorylated protein kinase B levels

Eagle, Andrew L.; Roberts, Megan M.; Mulo, Kostika; Liberzon, Israel; Galloway, Matthew P.; Perrine, Shane A.

doi:10.1016/j.neures.2012.11.001

Cited by 66 publications

(61 citation statements)

References 57 publications

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“…Therefore, our results suggest that SPS selectively attenuates social and object novelty-seeking, which requires recognition memory, while sparing sensation-seeking, which does not. In addition, locomotion behavior (i.e., exploratory behavior) was similarly unaffected by SPS, in line with our previous findings that locomotor activity is not affected by SPS [19]. …”

Section: Discussionsupporting

confidence: 91%

Single prolonged stress impairs social and object novelty recognition in rats

Eagle

Fitzpatrick

Perrine

2013

Behavioural Brain Research

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Posttraumatic stress disorder (PTSD) results from exposure to a traumatic event and manifests as re-experiencing, arousal, avoidance, and negative cognition/mood symptoms. Avoidant symptoms, as well as the newly defined negative cognitions/mood, are a serious complication leading to diminished interest in once important or positive activities, such as social interaction; however, the basis of these symptoms remains poorly understood. PTSD patients also exhibit impaired object and social recognition, which may underlie the avoidance and symptoms of negative cognition, such as social estrangement or diminished interest in activities. Previous studies have demonstrated that single prolonged stress (SPS), models PTSD phenotypes, including impairments in learning and memory. Therefore, it was hypothesized that SPS would impair social and object recognition memory. Male Sprague Dawley rats were exposed to SPS then tested in the social choice test (SCT) or novel object recognition test (NOR). These tests measure recognition of novelty over familiarity, a natural preference of rodents. Results show that SPS impaired preference for both social and object novelty. In addition, SPS impairment in social recognition may be caused by impaired behavioral flexibility, or an inability to shift behavior during the SCT. These results demonstrate that traumatic stress can impair social and object recognition memory, which may underlie certain avoidant symptoms or negative cognition in PTSD and be related to impaired behavioral flexibility.

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Section: Discussionsupporting

confidence: 91%

Single prolonged stress impairs social and object novelty recognition in rats

Eagle

Fitzpatrick

Perrine

2013

Behavioural Brain Research

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“…Despite the overall difference in the global pattern of H3K9me3 levels in the two selectively bred lines, the association with specific genes was quite specific and not necessarily reflective of the overall levels of the modified histone. Thus, GR, which we and others have implicated in greater basal anxiety (17,21,43) and which is elevated basally in the bLRs (17), exhibited a lower level of association with H3K9me3 which is consistent with the higher expression levels of that gene. This result was observed in all three brain regions studied: the HC, amygdala, and NAcc.…”

Section: Association Of Modified Histones At the Promoters Of Fgf2 Ansupporting

confidence: 80%

FGF2 is a target and a trigger of epigenetic mechanisms associated with differences in emotionality: Partnership with H3K9me3

Chaudhury

Aurbach

Sharma

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Posttranslational modifications of histone tails in chromatin template can result from environmental experiences such as stress and substance abuse. However, the role of epigenetic modifications as potential predisposing factors in affective behavior is less well established. To address this question, we used our selectively bred lines of high responder (bHR) and low responder (bLR) rats that show profound and stable differences in affective responses, with bLRs being prone to anxiety-and depression-like behavior and bHRs prone to addictive behavior. We first asked whether these phenotypes are associated with basal differences in epigenetic profiles. Our results reveal broad between-group differences in basal levels of trimethylated histone protein H3 at lysine 9 (H3K9me3) in hippocampus (HC), amygdala, and nucleus accumbens. Moreover, levels of association of H3K9me3 at Glucocorticoid Receptor (GR) and Fibroblast growth Factor 2 (FGF2) promoters differ reciprocally between bHRs and bLRs in these regions, consistent with these genes' opposing levels of expression and roles in modulating anxiety behavior. Importantly, this basal epigenetic pattern is modifiable by FGF2, a factor that modulates anxiety behavior. Thus, early-life FGF2, which decreases anxiety, altered the levels of H3K9me3 and its binding at FGF2 and GR promoters of bLRs rendering them more similar to bHRs. Conversely, knockdown of HC FGF2 altered both anxiety behavior and levels of H3K9me3 in bHRs, rendering them more bLR-like. These findings implicate FGF2 as a modifier of epigenetic mechanisms associated with emotional responsiveness, and point to H3K9me3 as a key player in the regulation of affective vulnerability.C hromatin remodeling is a mediator of lasting neural changes in response to experience, such as exposure to stress and drugs of abuse (1-7). Indeed, the interaction of certain modified histones with specific gene promoters has been shown to be an important mechanism of experience-dependent neuroplasticity (8-13). Although numerous studies have examined the impact of the environment on neural epigenetic profiles, relatively few studies have focused on preexisting differences in epigenetic profiles as potential predisposing factors in emotional reactivity. Such studies require the availability of an animal model where difference in "temperament" or propensity for specific affective responses can be reliably predicted and altered. Our laboratory has generated such an animal model that captures vulnerability for "internalizing disorders" vs. "externalizing disorders." Selectively bred high responder (bHR) rats exhibit greater responsiveness to novelty and to drug seeking behavior (externalizing behaviors), whereas selectively bred low responders (bLR) exhibit greater anxiety and depression-like responses (internalizing behaviors) (14, 15). These genetically bred phenotypes amplify behavioral traits observed in outbred animals (16)(17)(18)(19)(20).Several genes have been implicated in modifying these phenotypes, both in the bred and outbr...

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“…Although more than 90% of TH positive cells in LC expressed GR, there was no change in the GR expression in LC at this time point in contrast to SPS-triggered elevation of GR in the hippocampus (Liberzon et al 1999;Kohda et al 2007;Eagle et al 2013;Serova et al 2013b;Laukova et al 2014). However, we cannot completely rule out possible involvement of GR in TH regulation with SPS, since phosphorylation and translocation of GR to the nucleus (Nicolaides et al 2014) are important in regulating GR function and corticosterone levels are still higher than in unstressed controls even at this time point (Serova et al 2013b;Laukova et al 2014).…”

Section: Sps-induced Changes In the Lcmentioning

confidence: 64%

Locus coeruleus response to single‐prolonged stress and early intervention with intranasal neuropeptide Y

Sabban

Lauková

Alaluf

et al. 2015

Journal of Neurochemistry

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Dysregulation of the central noradrenergic system is a core feature of post-traumatic stress disorder (PTSD). Here, we examined molecular changes in locus coeruleus (LC) triggered by single-prolonged stress (SPS) PTSD model at a time when behavioral symptoms are manifested, and the effect of early intervention with intranasal neuropeptide Y (NPY). Immediately following SPS stressors, male SD rats were administered intranasal NPY (SPS/NPY) or vehicle (SPS/V). Seven days later, TH protein, but not mRNA, was elevated in LC only of the SPS/V group. Although 90% of TH positive cells expressed GR, its levels were unaltered. Compared to unstressed controls, LC of SPS/V, but not SPS/NPY, expressed less Y2 receptor mRNA with more CRHR1 mRNA in subset of animals, and elevated corticotropin-releasing hormone (CRH) in central nucleus of amygdala. Following testing for anxiety on elevated plus maze (EPM), there were significantly increased TH, DBH and NPY mRNAs in LC of SPS-treated, but not previously unstressed animals. Their levels highly correlated with each other but not with behavioral features on EPM. Thus, SPS triggers long-term noradrenergic activation and higher sensitivity to mild stressors, perhaps mediated by the up-regulation influence of amygdalar CRH input and down-regulation of Y2R presynaptic inhibition in LC. Results also demonstrate the therapeutic potential of early intervention with intranasal NPY for traumatic stress-elicited noradrenergic impairments.

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Single prolonged stress enhances hippocampal glucocorticoid receptor and phosphorylated protein kinase B levels

Cited by 66 publications

References 57 publications

Single prolonged stress impairs social and object novelty recognition in rats

Single prolonged stress impairs social and object novelty recognition in rats

FGF2 is a target and a trigger of epigenetic mechanisms associated with differences in emotionality: Partnership with H3K9me3

Locus coeruleus response to single‐prolonged stress and early intervention with intranasal neuropeptide Y

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